3 (5)-heteroaryl substituted pyrazoles as p38 kinase inhibitors

ABSTRACT

A class of pyrazole derivatives is described for use in treating p38 kinase mediated disorders. Compounds of particular interest are defined by Formula Iwherein R1, R2, Ar1 and HetAr2 are as described in the specification.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.9/561,423 (filed Apr. 28, 2000, now U.S. Pat. No. 6,335,336), which, inturn, is a continuation of U.S. patent application Ser. No. 09/283,718(filed Apr. 1, 1999, now U.S. Pat. No. 6,087,496), which, in turn, is acontinuation of U.S. patent application Ser. No. 09/083,923 (filed May22, 1998, now U.S. Pat. No. 5,932,576), which, in turn, claims priorityto U.S. Provisional Patent Application Serial No. 60/047,535 (filed May22, 1997). The entire text of each of the above patent applications isincorporated by reference into this patent application.

FIELD OF THE INVENTION

This invention relates to a novel group of pyrazole compounds,compositions and methods for treating p38 kinase mediated disorders.

BACKGROUND OF THE INVENTION

Mitogen-activated protein kinases (MAP) is a family of porline-directedserine/threonine kinases that activate their substrates by dualphosphorylation. The kinases are activated by a variety of signalsincluding nutritional and osmotic stress, UV light, growth factors,endotoxin and inflammatory cytokines. The p38 SNAP kinase group is a MAPfamily of various isoforms, including p38α, p38β and p38γ, and isresponsible for phosphorylating and activating transcription factors(e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g. MAPKAP-2 andMAPKAP-3). The p38 isoforms are activated by bacteriallipopolysaccharide, physical and chemical stress and by pro-inflammatorycytokines, including tumor necrosis factor (TNF-α) and interleukin-1(IL-1). The products of the p38 phosphorylation mediate the productionof inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.

TNF-α is a cytokine produced primarily by activated monocytes andmacrophages. Excessive or unregulated TNF production has been implicatedin mediating a number of diseases. Recent studies indicate that TNF hasa causative role in the pathogenesis of rheumatoid arthritis. Additionalstudies demonstrate that inhibition of TNF has broad application in thetreatment of inflammation, inflammatory bowel disease, multiplesclerosis and asthma.

TNF has also been implicated in viral infections, such as HIV, influenzavirus, and herpes virus including herpes simplex virus type-1 (HSV-1),herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV),varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6(HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8),pseudorabies and rhinotracheitis, among others.

IL-8 is another pro-inflammatory cytokine, which is produced bymononuclear cells, fibroblasts, endothelial cells, and keratinocytes,and is associated with conditions including inflammation.

IL-1 is produced by activated monocytes and macrophages and is involvedin the inflammatory response. IL-1 plays a role in manypathophysiological responses including rheumatoid arthritis, fever andreduction of bone resorption.

TNF, IL-1 and IL-8 affect a wide variety of cells and tissues and areimportant inflammatory mediators of a wide variety of disease states andconditions. The inhibition of these cytokines by inhibition of the p38kinase is of benefit in controlling, reducing and alleviating many ofthese disease states.

Various pyrazoles have previously been described. U.S. Pat. No.4,000,281, to Beiler and Binon, describes 4,5-aryl, heteroarylsubstituted pyrazoles with antiviral activity against both RNA and DNAviruses such as myxoviruses, adenoviruses, rhinoviruses, and variousviruses of the herpes group. WO 92/19615, published Nov. 12, 1992,describes pyrazoles as novel fungicides. U.S. Pat. No. 3,984,431, toCueremy and Renault, describes derivatives of pyrazole-5-acetic acid ashaving antiinflammatory activity. Specifically,[1-isobutyl-3,4-diphenyl-1H-pyrazol-5-yl]acetic acid is described. U.S.Pat. No. 3,245,093 to Hinsgen et al, describes a process for preparingpyrazoles. WO 83/00330, published Feb. 3, 1983, describes new processfor the preparation of diphenyl-3,4-methyl-5-pyrazole derivatives. WO95/06036, published for preparing pyrazole and its derivatives. U.S.Pat. No. 5,589,439, to T. Goto, et al., describes tetrazole derivativesand their use as herbicides. EP 515041 describes pyrimidyl substitutedpyrazole derivatives as novel agricultural fungicides. Japanese Patent4,145,081 describes pyrazolecarbxylic acid derivatives as herbicidesused in paddy fields, dry fields as well as non-agricultural areas.Japanese Patent 5,345,772 describes novel pyrazole derivatives havingpotent inhibitory activity against acetylcholinesterase.

Pyrazoles have been described for use in the treatment of inflammation.Japanese Patent 5,017,470 describes synthesis of pyrazole derivatives asanti-inflammatory, anti-rheumatic, anti-bacterial and anti-viral drugs.EP 115640, published Dec. 30, 1983, describes 4-imidazolyl-pyrazolederivatives as inhibitors of thromboxane synthesis.3-(4-Isopropyl-1-methylcyclohex-1-yl)-4-(imidazol-1-yl)-1H-pyrazole isspecifically described. WO 97/01551, published Jan. 16, 1997, describespyrazole compounds as adenosine antagonists.4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3-phenylpyrazole is specificallydescribed. U.S. Pat. No. 5,134,142, to Matsuo et al. describes1,5-diaryl pyrazoles as having anti-inflammatory activity.

U.S. Pat. No. 5,559,137 to Adams et al, describes novel pyrazoles(1,3,4,-substituted) as inhibitors of cytokines used in the treatment ofcytokine diseases. Specifically,3-(4-fluorophenyl)-1-(4-methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazoleis described. WO 96/03385, published Feb. 8, 1996, describes3,4-substituted pyrazoles, as having anti-inflammatory activity.Specifically,4-[1-ethyl-4-(4-pyridyl)-5-trifluoromethyl-1H-pyrazol-3-yl]benzenesulfonamideis described.

The invention's pyrazolyl compounds are found to show usefulness as p38kinase inhibitors.

DESCRIPTION OF THE INVENTION

A class of substituted pyrazolyl compounds useful in treating p38mediated disorders is defined by Formula I:

wherein

R¹ is selected from hydrido, alkyl, cycloalkyl, alkenyl, alkynyl,heterocyclyl, cycloalkylalkylene, halcolkyl, hydroxyalkyl, aralkyl,alkoxyalkyl, mercaptoalkyl, alkylthioalkylene, amino, alkylamino,arylamino, aminoalkyl, alkylaminoalkylene, heterocyclylalkylene,aminocarbonylalkylene, and alkylaminocarbonylalkylene; and

R² is selected from hydrido, alkyl, alkenyl, alkynyl, heterocyclyl,haloalkyl, heterocyclylalkyl, amino, alkylamino, aminoalkyl, alkoxy,alkylthio, carboxy, alkoxycarbonyl, carboxyalkyl, aminocarbonylamino,alkylaminocarbonylamino, alkylsulfonyl, aminosulfonyl,alkylsulfonylamino, aminosulfonylamino, alkylaminosulfonylamino, andalkynylamino; wherein the heterocyclyl and heterocyclylalkyl groups areoptionally substituted with one or more radicals independently selectedfrom alkylthio, alkylsulfonyl, alkylsulfinyl, halo, alkyl, alkoxy,aryloxy, aralkoxy, heterocyclyl, haloalkyl, amino, cyano, and hydroxy;and

Ar¹ is aryl optionally substituted with one or more radicalsindependently selected from halo, alkyl, alkenyl, alkynyl, alkoxy,alkenoxy, alkyldioxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino,aminocarbonyl, cyano, alkoxycarbonyl, formyl, aminosulfonyl, alkylamino,nitro, arylamino, alkylcarbonylamino, halosulfonyl, aminoalkyl, andhaloalkyl; and

HetAr² is pyridinyl, pyrimidinyl or quinolinyl optionally substitutedwith one or more radicals independently selected from alkylthio,alkylsulfonyl, alkylsulfinyl, halo, alkyl, heterocyclyl, alkoxy,aralkoxy, haloalkyl, amino, cyano, aralkyl, alkylamino, cycloalkylamino,cycloalkenylamino, arylamino, alkynylamino, and aralkylamino; or

a pharmaceutically-acceptable salt or a tautomer thereof.

Compounds of Formula I would be useful for, but not limited to, thetreatment of any disorder or disease state in a human, or other mammal,which is excacerbated or caused by excessive or unregulated TNF or p38kinase production by such mammal. Accordingly, the present inventionprovides a method of treating a cytokine-mediated disease whichcomprises administering an effective cytokine-interfering amount of acompound of Formula I, or a pharmaceutically acceptable salt or tautomerthereof.

Compounds of Formula I would be useful for, but not limited to, thetreatment of inflammation in a subject, and for use as antipyretics forthe treatment of fever. Compounds of the invention would be useful totreat arthritis, including but not limited to, rheumatoid arthritis,spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis, osteoarthritis, gouty arthritisand other arthritic conditions. Such compounds would be useful for thetreatment of pulmonary disorders or lung inflammation, including adultrespiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis,and chronic pulmonary inflammatory disease. The compounds are alsouseful for the treatment of viral and bacterial infections, includingsepsis, septic shock, gram negative sepsis, malaria, meningitis,cachexia secondary to infection or malignancy, cachexia secondary toacquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS relatedcomplex), pneumonia, and herpesvirus. The compounds are also useful forthe treatment of bone resorption diseases, such as osteoporosis,endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmunedisease including graft vs. host reaction and allograft rejections,cardiovascular diseases including atherosclerosis, thrombosis,congestive heart failure, and cardiac reperfusion injury, renalreperfusion injury, liver disease and nephritis, and myalgias due toinfection.

The compounds are also useful for the treatment of influenza, multiplesclerosis, cancer, diabetes, systemic lupus erthrematosis (SLE),skin-related conditions such as psoriasis, eczema, burns, dermatitis,keloid formation, and scar tissue formation. Compounds of the inventionalso would be useful to treat gastrointestinal conditions such asinflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome and ulcerative colitis. The compounds would also be useful inthe treatment of ophthalmic diseases, such as retinitis, retinopathies,uveitis, ocular photophobia, and of acute injury to the eye tissue.Compounds of the invention also would be useful for treatment ofangiogenesis, including neoplasia; metastasis; ophthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, retrolental fibroplasia andneovascular glaucoma; ulcerative diseases such as gastric ulcer;pathological, but non-malignant, conditions such as hemaginomas,including invantile hemaginomas, angiofibroma of the nasopharynx andavascular necrosis of bone; diabetic nephropathy and cardiomyopathy; anddisorders of the female reproductive system such as endometriosis. Thecompounds of the invention may also be useful for preventing theproduction of cyclooxygenase-2.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like. More preferredanimals include horses, dogs, and cats.

The present compounds may also be used in co-therapies, partially orcompletely, in place of other conventional antiinflammatories, such astogether with steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDS,immunosuppressive agents, 5-lipoxygenase inhibitors, LTB₄ antagonistsand LTA₄ hydrolase inhibitors.

As used herein, the term “TNF mediated disorder” refers to any and alldisorders and disease states in which TNF plays a role, either bycontrol of TNF itself, or by TNF causing another monokine to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to TNF, wouldtherefore be considered a disorder mediated by TNF.

As used herein, the term “p38 mediated disorder” refers to any and alldisorders and disease states in which p38 plays a role, either bycontrol of p38 itself, or by p38 causing another factor to be released,such as but not limited to IL-1, IL-6 or IL-8. A disease state in which,for instance, IL-1 is a major component, and whose production or action,is exacerbated or secreted in response to p38, would therefore beconsidered a disorder mediated by p38.

As TNF-β has close structural homology with TNF-α (also known ascachectin), and since each induces similar biologic responses and bindsto the same cellular receptor, the synthesis of both TNF-α and TNF-β areinhibited by the compounds of the present invention and thus are hereinreferred to collectively as “TNF” unless specifically delineatedotherwise.

A preferred class of compounds consists of those compounds of Formula Iwherein

R¹ is selected from hydrido, lower alkyl, lower cycloalkyl, lowercycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower alkenyl,lower alkynyl, lower heterocyclyl, lower aralkyl, lower alkoxyalkyl,lower mercaptoalkyl, lower alkylthioalkylene, amino, lower alkylamino,lower arylamino, lower aminoalkyl, lower alkylaminoalkylene, lowerheterocyclylalkylene, lower aminocarbonylalkylene, and loweralkylaminocarbonylalkylene; and

R² is selected from hydrido, lower alkyl, lower alkenyl, lower alkynyl,lower haloalkyl, lower heterocyclyl, lower heterocyclylalkylene, amino,lower alkylamino, lower alkynylamino, lower aminoalkyl, lower alkylthio,lower carboxy, lower alkoxycarbonyl, lower carboxyalkyl, loweraminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonyl,lower aminosulfonyl, lower alkylsulfonylamino, lower aminosulfonylamino,and lower alkylaminosulfonylamino, wherein the heterocyclyl andheterocyclylalkyl groups are optionally substituted with one or moreradicals independently selected from lower alkylthio, loweralkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, lower alkoxy,aryloxy, lower heterocyclyl, lower haloalkyl, amino, and cyano; and

Ar¹ is selected from phenyl, biphenyl, and naphthyl, wherein Ar¹ isoptionally substituted with one or more radicals independently selectedfrom lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halo, loweralkyl, lower alkenyl, lower alkynyl, lower alkylsulfinyl, cyano, loweralkoxycarbonyl, aminocarbonyl, formyl, lower alkylcarbonylamino, lowerhaloalkyl, lower alkoxy, lower alkenyloxy, lower alkyldioxy, amino,lower alkylamino, lower aminoalkyl, arylamino, nitro, and halosulfonyl;and

HetAr² is pyridinyl or pyrimidinyl optionally substituted with one ormore radicals independently selected from lower alkylthio, loweralkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, lowerheterocyclyl, lower alkoxy, lower aralkoxy, lower haloalkyl, amino,cyano, lower aralkyl, lower alkylamino, lower cycloalkylamino, lowerarylamino, lower alkynylamino, and lower aralkylamino; or

a pharmaceutically-acceptable salt or tautomer thereof.

A class of compounds of particularly interest consists of thesecompounds of Formula I wherein

R¹ is selected from hydrido, methyl, ethyl, isopropyl, tert-butyl,isobutyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl,difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, vinyl,allyl, ethynyl, propargyl, morpholinyl, piperidinyl, piperazinyl,benzyl, phenylethyl, morpholinomethyl, morpholinoethyl,pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl,pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino,methylamino, dimethylamino, phenylamino, methylaminomethyl,dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, cyclopropyl,cyclopentyl, cyclohexyl, cyclohexylmerhyl, hydroxymethyl, hydroxyethyl,methylthio, and methylthiomethyl; and

R² is selected from hydrido, methyl, ethyl, propyl, isopropyl,tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, amino,N-methylamino, N,N-dimethylamino, ethynylamino, propargylamino,piperidinyl, piperazinyl, morpholinomethyl, pyrrolidinylmethyl,piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl,thiazolylmethyl, oxazolylmethyl, pyrimidinylmethyl, quinolylmethyl,isoquinolinylmethyl, imidazolylmethyl, benzimidazolylmethyl,furylmethyl, pyrazinylmethyl, aminocarbonylamino,methylaminocarbonylamino, dimethylaminocarbonylamino,ethylaminocarbonylamino, diethylaminocarbonylamino, methylsulfonylamino,ethylsulfonylamino, aminosulfonylamino, methylaminosulfonylamino,dimethylaminosulfonylamino, ethylaminosulfonylamino, anddiethylaminosulfonylamino; and

Ar¹ is selected from phenyl, biphenyl, and naphthyl, wherein Ar¹ isoptionally substituted with one or more radicals independently selectedfrom methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo,aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano,methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,dichloromethyl, chloromethyl, allyl, vinyl, ethynyl, propargyl, methoxy,ethoxy, propyloxy, n-butoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, aminomethyl, aminoethyl, N-methyl,N-phenylamino, phenylamino, diphenylamino, nitro, and chlorosulfonyl;and

HetAr² is selected from pyridinyl and pyrimidinyl, wherein HetAr² isoptionally substituted with one or more radicals independently selectedfrom methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo,methyl, ethyl, isopropyl, tert-butyl, isobutyl, methoxyl, ethoxyl,phenoxyl, benzoxyl, phenethyl, trifluoromethyl, fluoromethyl,difluoromethyl, amino, benzylamino, propargylamino, cyclopropylamino,cyclobutylamino, cyclopentylamino, and cyano; or

a pharmaceutically-acceptable salt or tautomer thereof.

A class of compounds of specific interest consists of those compounds ofFormula I wherein

R¹ is hydrido, methyl, ethyl, hydroxyethyl, propargyl,dimethylaminoethyl or morpholinoethyl; and

R² is selected from hydrido, methyl, ethyl, amino, aminocarbonylamino,methylaminocarbonylamino, methylsulfonylamino, aminosulfonylamino, andmethylaminosulfonylamino; and

Ar¹ is phenyl optionally substituted with one or more radicalsindependently selected from methylthio, methylsulfinyl, methylsulfonyl,fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl,tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl,aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl,fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, methoxy,ethoxy, propyloxy, n-butoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, aminomethyl, aminoethyl, N-methyl,N-phenylamino, phenylamino, diphenylamino, nitro, and chlorosulfonyl;and

HetAr² is optionally substituted with one or more radicals independentlyselected from methylthio, methylsulfinyl, methylsulfonyl, fluoro,chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, methoxyl,ethoxyl, phenoxyl, benzoxyl, trifluoromethyl, fluoromethyl,difluoromethyl, amino, propargylamino, and cyano; or

a pharmaceutically-acceptable salt or a tautomer thereof.

A class of compounds of very specific interest consists of thosecompounds of Formula I wherein

R¹ is hydrido or methyl; and

R² is hydrido or methyl; and

Ar¹ is phenyl which is optionally substituted with one or more radicalsindependently selected fluoro, chloro, methyl, ethyl, trifluoromethyl,methoxy, ethoxy, dimethylamino, and nitro; and

HetAr² is optionally substituted with one or more radicals independentlyselected from methyl, chloro, fluoro, and trifluoromethyl; or

a pharmaceutically-acceptable salt or tautomer thereof.

A family of specific compounds of particular interest within Formula Iconsists of compounds, and tautomers and pharmaceutically-acceptablesalts thereof, as follows:

4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine;

4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine;

N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide;

N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylsulfamide;

[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]urea;

[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]sulfamide;

4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazol-5-amine;

N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylurea;

4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine;

4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine;

4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol;

4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine;

4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine;

4-[4-(4-chlorophenyl)-1H-pyrazol-3-yl]pyridine;

4-(4-phenyl-1H-pyrazol-5-yl)pyridine;

1-methyl-4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]]piperidine;and

1-methyl-4-[2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-1-yl]piperidine.

The term “hydrido” denotes a single hydrogen atom (H). This hydridoradical may be attached, for example, to an oxygen atom to form ahydroxyl radical or two hydrido radicals may be attached to a carbonatom to form a methylene (—CH₂—) radical. Where used, either alone orwithin other terms such as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl”,“hydroxyalkyl”, “mercaptoalkyl”, the term “alkyl” embraces linear orbranched radicals having one to about twenty carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkylradicals are “lower alkyl” radicals having one to about ten carbonatoms. Most preferred are lower alkyl radicals having one to about sixcarbon atoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl and the like. The term “alkenyl” embraces linear or branchedradicals having at least one carbon-carbon double bond of two to abouttwenty carbon atoms or, preferably, two to about twelve carbon atoms.More preferred alkenyl radicals are “lower alkenyl” radicals having twoto about six carbon atoms. Examples of alkenyl radicals include ethenyl,propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms“alkenyl” and “lower alkenyl”, embrace radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations. The term“alkynyl” embraces linear or branched radicals having at least onecarbon-carbon triple bond of two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkynylradicals are “lower alkynyl” radicals having two to about six carbonatoms. Examples of alkynyl radicals include propargyl, 1-propynyl,2-propynyl, 1-butyne, 2-butenyl and 1-pentynyl. The term “cycloalkyl”embraces saturated carbocyclic radicals having three to about twelvecarbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl”radicals having three to about eight carbon atoms. Examples of suchradicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.The term “cycloalkylalkylene” embraces alkyl radicals substituted with acycloalkyl radical. More preferred cycloalkylalkylene radicals are“lower cycloalkylalkylene” which embrace lower alkyl radicalssubstituted with a lower cycloalkyl radical as defined above. Examplesof such radicals include cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl and cyclohexylmethyl. The term “cycloalkenyl” embracespartially unsaturated carbocyclic radicals having three to twelve carbonatoms and one or two double bonds but not necessarily conjugated(“cycloalkyldienyl”). More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.The term “cycloalkenylalkylene” embraces alkyl radicals substituted witha cycloalkenyl radical. More preferred cycloalkenylalkylene radicals are“lower cycloalkenylalkylene” which embrace lower alkyl radicalssubstituted with a lower cycloalkenyl radical, as defined above.Examples of such radicals include cyclobutenylmethyl,cyclopentenylmethyl and cyclohexenylmethyl. The term “halo” meanshalogens such as fluorine, chlorine, bromine or iodine. The term“haloalkyl” embraces radicals wherein any one or more of the alkylcarbon atoms is substituted with halo as defined above. Specificallyembraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. Amonohaloalkyl radical, for one example, may have either an iodo, bromo,chloro or fluoro atom within the radical. Dihalo and polyhaloalkylradicals may have two or more of the same halo atoms or a combination ofdifferent halo radicals. “Lower haloalkyl” embraces radicals having oneto six carbon atoms. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. The term“hydroxyalkyl” embraces linear or branched alkyl radicals having one toabout ten carbon atoms, any one of which may be substituted with one ormore hydroxyl radicals. More preferred hydroxyalkyl radicals are “lowerhydroxyalkyl” radicals having one to six carbon atoms and one or morehydroxyl radicals. Examples of such radicals include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms“alkoxy” and “alkyloxy” embrace linear or branched oxy-containingradicals each having alkyl portions of one to about ten carbon atoms.More preferred alkoxy radicals are “lower alkoxy” radicals having one tosix carbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. The term “alkoxyalkyl” embraces alkylradicals having one or more alkoxy radicals attached to the alkylradical to form, for example, monoalkoxyalkyl and dialkoxyalkylradicals. The “alkoxy” radicals may be further substituted with one ormore halo atoms, such as fluoro, chloro or bromo, to provide“haloalkoxy” radicals.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. More preferredaryl are 6-12 membered aryl radicals. Examples of such radicals includephenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moietiesmay also be substituted at a substitutable position with one or moresubstituents selected independently from, for example, halo, alkyl,alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy, alkylthio,alkylsulfinyl, alkylsulfonyl, amino, aminocarbonyl, cyano,alkoxycarbonyl, formyl, aminosulfonyl, alkylamino, nitro, arylamino,alkylcarbonylamino, halosulfonyl, aminoalkyl, and haloalkyl,alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, aralkoxy, hydroxyl,acyl, carboxy, aminocarbonyl, andaralkoxycarbonyl. The term “alkyldioxy” encompasses an alkyldioxybridge, such as a methylenedioxy bridge, between two carbon ring atomsof an aryl moiety.

The term “heterocyclyl” embraces saturated, partially unsaturated andunsaturated heteroatom-containing ring-shaped radicals, which can alsobe called “heterocyclyl”, “heterocycloalkenyl” and “heteroaryl”correspondingly, where the heteroatoms may be selected from nitrogen,sulfur and oxygen. Examples of saturated heterocyclyl radicals includesaturated 3 to 6-membered heteromonocyclic group containing 1 to 4nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g.morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,thiazolidinyl, etc.). Examples of partially unsaturated heterocyclylradicals include dihydrothiophene, dihydropyran, dihydrofuran anddihydrothiazole. Heterocyclyl radicals may include a pentavalentnitrogen, such as in tetrazolium and pyridinium radicals. The term“heteroaryl” embraces unsaturated heterocyclyl radicals. Examples ofheteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclicgroup containing 1 to 4 nitrogen atoms, for example, pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl,etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to 5nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.;unsaturated 3 to 6-membered heteromonocyclic group containing an oxygenatom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing a sulfur atom, for example, thienyl,etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g.benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.;unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl,etc.) and the like. The term “heteroaryl” also embraces radicals whereheterocyclyl radicals are fused with aryl radicals. Examples of suchfused bicyclic radicals include benzofuran, benzothiophene, and thelike. Said heterocyclyl group may have 1 to 3 substituents such asalkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino. The term“heterocyclylalkylene” embraces heterocyclyl-substituted alkyl radicals.More preferred heterocyclylalkylene radicals are “lowerheterocyclylalkylene” radicals having one to six carbon atoms and aheterocyclyl radical.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. More preferred alkylthio radicals are “lower alkylthio”radicals having alkyl radicals of one to six carbon atoms. Examples ofsuch lower alkylthio radicals are methylthio, ethylthio, propylthio,butylthio and hexylthio. The term “alkylthioalkylene” embraces radicalscontaining an alkylthio radical attached through the divalent sulfuratom to an alkyl radical of one to about ten carbon atoms. Morepreferred alkylthioalkylene radicals are “lower alkylthioalkylene”radicals having alkyl radicals of one to six carbon atoms. Examples ofsuch lower alkylthioalkylene radicals include methylthiomethyl. The term“alkylsulfinyl” embraces radicals containing a linear or branched alkylradical, of one to about ten carbon atoms, attached to a divalent—S(═O)— radical. More preferred alkylsulfinyl radicals are “loweralkylsulfinyl”, radicals having alkyl radicals of one to six carbonatoms. Examples of such lower alkylsulfinyl radicals includemethylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term“sulfonyl”, whether used alone or linked to other terms such as“alkylsulfonyl”, or “halosulfonyl” denotes a divalent radical, —SO₂—.“Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical,where alkyl is defined as above. More preferred alkylsulfonyl radicalsare “lower alkylsulfonyl” radicals having one to six carbon atoms.Examples of such lower alkylsulfonyl radicals include methylsulfonyl,ethylsulfonyl and propylsulfonyl. The “alkylsulfonyl” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide haloalkylsulfonyl radicals. The term “halosulfonyl”embraces halo radicals attached to a sulfonyl radical. Examples of suchhalosulfonyl radicals include chlorosulfonyl and bromosulfonyl. Theterms “sulfamyl”, “aminosulfonyl” and “sulfonamidyl” denote NH₂O₂S—.

The term “carbonyl”, whether used alone or with other terms, such as“alkoxycarbonyl”, denotes —(C═O)—. The terms “carboxy” or “carboxyl”,whether used alone or with other terms, such as “carboxyalkyl”, denotes—CO₂H. The term “carboxyalkyl” embraces alkyl radicals substituted witha carboxy radical. More preferred are “lower carboxyalkyl” radicalswhich embrace carboxy-substituted lower alkyl radicals, as definedabove. Examples of such lower carboxyalkyl radicals includecarboxymethyl, carboxyethyl and carboxypropyl. The term “alkoxycarbonyl”means a radical containing an alkoxy radical, as defined above, attachedvia an oxygen atom to a carbonyl radical. More preferred are “loweralkoxycarbonyl” radicals with alkyl portions having one to six carbons.Examples of such lower alkoxycarbonyl (ester) radicals includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl andhexyloxycarbonyl. The term “alkoxycarbonylalkylene” embraces alkylradicals substituted with an alkoxycarbonyl radical as defined above.More preferred are “lower alkoxycarbonylalkylene” radicals with alkylportions having one to six carbons. Examples of such loweralkoxycarbonylalkylene radicals include methoxycarbonylmethylene,ethoxycarbonylmethylene, methoxycarbonylethylene andethoxycarbonylethylene. The term “alkylcarbonyl”, includes radicalshaving alkyl radicals attached to a carbonyl radical. Examples of suchradicals include methylcarbonyl, ethylcarbonyl, propylcarbonyl,butylcarbonyl, and pentylcarbonyl. The term “aralkyl” embracesaryl-substituted alkyl radicals. Preferred aralkyl radicals are “loweraralkyl”, having lower alkyl groups substituted with one or more arylgroups. Examples of such groups include benzyl, diphenylmethyl,triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in saidaralkyl may be additionally substituted with halo, alkyl, alkoxy,haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl areinterchangeable. The term “heterocyclylalkylene” embraces saturated,partially unsaturated and unsaturated heterocyclyl-substituted alkylradicals such as pyrrolidinylmethyl, pyridylmethyl, quinolylmethyl,thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl inheteroaralkyl (unsaturated heterocyclyl-substituted alkyl radicals) maybe additionally substituted with halo, alkyl, alkoxy, haloalkyl andhaloalkoxy. The term “aryloxy” embraces aryl radicals attached throughan oxygen atom to other radicals. The term “aralkoxy” embraces aralkylradicals attached through an oxygen atom to other radicals.

The term “aminoalky”, embraces alkyl radicals substituted with aminoradicals. More preferred are “lower aminoalkyl” radicals. Examples ofsuch radicals include aminomethyl, aminoethyl, and the like. The term“alkylamino” denotes amino groups which are substituted with one or twoalkyl radicals. Preferred are “lower alkylamino” radicals having alkylportions having one to six carbon atoms. Suitable lower alkylamino maybe monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such asN-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or thelike. The term “arylamino” denotes amino groups which are substitutedwith one or two aryl radicals, such as N-phenylamino. The “arylamino”radicals may be further substituted on the aryl ring portion of theradical. The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH. The term “alkylaminocarbonyl” denotes an aminocarbonyl groupwhich has been substituted with one or two alkyl radicals on the aminonitrogen atom. Preferred are “N-alkylaminocarbonyl” and“N,N-dialkylaminocarbonyl” radicals. More preferred are “lowerN-alkylaminocarbonyl” and “lower N,N-dialkylaminocarbonyl” radicals withlower alkyl portions as defined above. The term “aminocarbonylamino”embraces radicals having one or more aminocarbonyl radicals attached toan amino radical. The term “alkylaminocarbonylamino” embraces radicalshaving one or more alkyl radicals attached to an aminocarbonylaminoradical. Preferred are “lower alkylaminocarbonylamino” radicals withlower alkyl portions as defined above. The term “alkylcarbonylamino”embraces amino groups which are substituted with one or morealkylcarbonyl radicals. More preferred alkylcarbonylamino radicals are“lower alkylcarbonylamino” having lower alkylcarbonyl radicals asdefined above attached to amino radicals. The term “alkylaminoalkylene”embraces radicals having one or more alkyl radicals attached to anaminoalkyl radical. The term “alkylsulfonylamino” embraces radicalshaving one or more alkylsulfonyl radicals attached to an amino radical.Preferred are “lower alkylsulfonylamino” radicals with lower alkylportions as defined above. The term “aminosulfonylamino” embracesradicals having one or more aminosulfonyl radicals attached to an aminoradical. The term “alkylaminosulfonylamino” embraces radicals having oneor more alkyl radicals attached to an aminosulfonylamino radical.Preferred are “lower alkylaminosulfonylamino” radicals with lower alkylportions as defined above.

The additional terms used to describe the substituents of the pyrazolering and not specifically defined herein are defined in a similar mannerto that illustrated in the above definitions. As above, more preferredsubstituents are those containing “lower” radicals. Unless otherwisedefined to contrary, the term “lower” as used in this application meansthat each alkyl radical of a pyrazole ring substituent comprising one ormore alkyl radicals has one to about six carbon atoms; each alkenylradical of a pyrazole ring substituent comprising one or more alkenylradicals has two to about six carbon atoms; each alkynyl radical of apyrazole ring substituent comprising one or more alkynyl radicals hastwo to about six carbon atoms; each cycloalkyl or cycloalkenyl radicalof a pyrazole ring substituent comprising one or more cycloalkyl and/orcycloalkenyl radicals is a 3 to 8 membered ring cycloalkyl orcycloalkenyl radical, respectively; each aryl radical of a pyrazole ringsubstituent comprising one or more aryl radicals is a monocyclic arylradical; and each heterocyclyl radical of a pyrazole ring substituentcomprising one or more heterocyclyl radicals is a 4-8 membered ringheterocyclyl.

The present invention comprises the tautomeric forms of compounds offormula I. As illustrated below, the pyrazoles of Formula I and I′ aremagnetically and structurally equivalent because of the prototropictautomeric nature of the hydrogen:

The present invention also comprises compounds of Formula I having oneor more asymmetric carbons. It is known to those skilled in the art thatthose pyrazoles of the present invention having asymmetric carbon atomsmay exist in diastereomeric, racemic, or optically active forms. All ofthese forms are contemplated within the scope of this invention. Morespecifically, the present invention includes enantiomers, diastereomers,racemic mixtures, and other mixtures thereof.

The present invention comprises a pharmaceutical composition for thetreatment of a TNF mediated disorder, a p38 kinase mediated disorder,inflammation, and/or arthritis, comprising a therapeutically-effectiveamount of a compound of Formula I, or a therapeutically-acceptable saltor tautomer thereof, in association with at least onepharmaceutically-acceptable carrier, adjuvant or diluent.

The present invention also comprises a therapeutic method of treating aTNF mediated disorder, a p38 kinase mediated disorder, inflammationand/or arthritis in a subject, the method comprising treating a subjecthaving or susceptible to such disorder or condition with atherapeutically-effective amount of a compound of Formula I

wherein

R¹ is selected from hydrido, alkyl, cycloalkyl, alkenyl, alkynyl,heterocyclyl, cycloalkylalkylene, haloalkyl, hydroxyalkyl, aralkyl,alkoxyalkyl, mercaptoalkyl, alkylthioalkylene, amino, alkylamino,arylamino, aminoalkyl, alkylaminoalkylene, heterocyclylalkylene,aminocarbonylalkylene, and alkylaminocarbonylalkylene; and

R² is selected from hydrido, alkyl, alkenyl, alkynyl, heterocyclyl,haloalkyl, heterocyclylalkyl, amino, alkylamino, aminoalkyl, alkoxy,alkylthio, carboxy, alkoxycarbonyl, carboxyalkyl, aminocarbonylamino,alkylaminocarbonylamino, alkylsulfonyl, aminosulfonyl,alkylsulfonylamino, aminosulfonylamino, alkylaminosulfonylamino, andalkynylamino; wherein the heterocyclyl and heterocyclylalkyl groups areoptionally substituted with one or more radicals independently selectedfrom alkylthio, alkylsulfonyl, alkylsulfinyl, halo, alkyl, alkoxy,aryloxy, aralkoxy, heterocyclyl, haloalkyl, amino, cyano, and hydroxy;and

Ar¹ is aryl optionally substituted with one or more radicalsindependently selected from halo, alkyl, alkenyl, alkynyl, alkoxy,alkenoxy, alkyldioxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino,aminocarbonyl, cyano, alkoxycarbonyl, formyl, aminosulfonyl, alkylamino,nitro, arylamino, alkylcarbonylamino, halosulfonyl, aminoalkyl, andhaloalkyl; and

HetAr² is pyridinyl, pyrimidinyl or quinolinyl optionally substitutedwith one or more radicals independently selected from alkylthio,alkylsulfonyl, alkylsulfinyl, halo, alkyl, heterocyclyl, alkoxy,aralkoxy, haloalkyl, amino, cyano, aralkyl, alkylamino, cycloalkylamino,cycloalkenylamino, arylamino, alkynylamino, and aralkylamino; or

a pharmaceutically-acceptable salt or a tautomer thereof.

Also included in the family of compounds of Formula I are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric andgalacturonic acid. Suitable pharmaceutically-acceptable base additionsalts of compounds of Formula I include metallic salts and organicsalts. More preferred metallic salts include, but are not limited toappropriate alkali metal (group Ia) salts, alkaline earth metal (groupIIa) salts and other physiological acceptable metals. Such salts can bemade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc. Preferred organic salts can be made from tertiary amines andquaternary ammonium salts, including in part, tromethamine,diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine. All of these salts may be prepared by conventional means formthe corresponding compound of Formula I by reacting, for example, theappropriate acid or base with the compound of Formula I.

GENERAL SYNTHETIC PROCEDURES

The compounds of the invention can be synthesized according to thefollowing procedures of Schemes I-VI wherein the R¹-R³ substituents andAr¹, HetAr² are as defined for Formula I, above, except where furthernoted.

Scheme I shows he three step preparation of the pyrazole 5 of thepresent invention. In step 1, the reaction of arylmethyl derived ketone1 with pyridine derived aldehyde 2 either in a solvent such as benzeneor toluene in the presence of a base such as pyridine or in a mixture ofacids such as acetic acid and hydrogen bromide gives the α,β-unsaturatedketone 3. In step 2, in the presence of base such as sodium hydroxide,α,β-unsaturated ketone 3 is converted to the corresponding epoxide 4 bythe treatment with hydrogen peroxide solution at room temperature. Instep 3, epoxide 4 is condensed with hydrazine in a suitable solvent suchas ethanol at temperature ranging up to the boiling point to formpyrazole 5. Alternatively, pyrazole 5 can be prepared by treatment of 3with tosyl hydrazide in the presence of an acid such as acetic acid atreflux.

Scheme II shows the synthesis of pyrazole 12 containing a heteroaromaticring by three routes. In Route 1, ketone 6 is condensed with hydrazine 7to give substituted hydrazine 9, which is then reacted with acyl halideor anhydride 10 at low temperature to provide acyl hydrazone 11. Uponheating at temperature up to 200° C., hydrazone 11 is converted topyrazole 12. In Route 2, acyl hydrazone 11 is formed directly byreaction of ketone 6 with acyl hydrazide 8 at room temperature. Acylhydrazide 8 may be formed by reaction of hydrazine with a carboxylicacid ester. Heating 11 as above then provides pyrazole 12. In Route 3,ketone 6 is treated with acyl hydrazide 8 at from room temperature to˜200° C. to give pyrazole 12 directly. Alternatively, this condensationmay be carried out in an acidic solvent, such as acetic acid, or in asolvent containing acetic acid.

Cyanoketone 13 may be synthesized according to the procedure describedby I. Lantos et al in J. Org. Chem., volume 53, pp. 4223-4227 (1988) forthe synthesis of the p-fluoro compound (X=p−F). This procedure, which isincorporated herein by reference, can be used to synthesize cyanoketonessuch as 13 wherein X is selected from, for example, halogen, alkyl andalkoxy. Cyanoketones such as 13 may be converted to pyrazoles 14 byreaction with a hydrazine in a suitable solvent, such as benzene ortoluene. A catalyst such as acetic acid may be employed. When hydrazineitself is employed, the ring nitrogen atoms of the pyrazole thusobtained bear no substituent except hydrogen on one of the ring nitrogenatoms. When a substituted hydrazine, such as methylhydrazine isemployed, the product pyrazole 14 bears a substituent on the ringnitrogen atom adjacent to the aminated ring carbon atom, as shown inScheme 1. The resultant aminopyrazole 14 may be acylated or sulfonylatedto form substituted aminopyrazole 15 by treatment with a suitablyactivated carboxylic or sulfonic acid in a suitable solvent such aspyridine. Examples of a suitably activated carboxylic acid includeacetic anhydride or benzoyl chloride. Examples of a suitably activatedsulfonic acid include methanesulfonyl chloride, p-toluenesulfonylchloride or sulfamyl chloride.

Scheme IV illustrates the synthesis of 3-pyridyl-4-aryl-pyrazoles of thepresent invention. Benzoate 16 is first reacted with pyridine 17 in thepresence of a base, such as an alkali metal alkoxide (preferably sodiummethoxide), in a suitable solvent, such as tetrahydrofuran. Subsequenttreatment with an acid, preferably a mineral acid such as hydrochloricacid, yields the desoxybenzoin 18. Desoxybenzoin 18 is then converted toketone 19 by treatment with an excess of dimethylformamide dimethylacetal. Ketone 19 is then reacted with hydrazine in a suitable solventsuch as ethanol to yield a mixture of pyrazoles 20 and 21. In Scheme IV,R⁴ represents one or more radicals independently selected from theoptional substituents previously defined for Ar¹; and R⁵ represents oneor more radicals independently selected from the optional substituentspreviously defined for HetAr².

The 3-pyrimidinyl-4-aryl-pyrazoles of the present invention can besynthesized in the manner of Scheme IV by replacing pyridine 17 with thecorresponding pyrimidine.

In Scheme V, hydroxyalkyl pyrazoles 22 and 23 are converted to sulfonatederivatives by reaction with an alkyl- or arylsulfonyl halide. Thesesulfonates are then reacted with ammonia or primary amines or secondaryamines to give the corresponding 1-amino-pyrazoles 24 and 25,respectively. In Scheme V, n is 1, 2, 3, 4 or 5; R⁴ and R⁵ are asdefined in Scheme IV; R⁶ and R⁷ are independently selected, for example,from hydrogen, alkyl and aryl, or together with the nitrogen atom towhich they are attached form a 4-8 membered ring that may contain one ormore additional heteroatoms selected from oxygen, nitrogen or sulfur.

Scheme VI is similar to Scheme IV except that desoxybenzoin 18 is firstreacted with hydrazine in a suitable solvent such as ethanol to yieldhydrazine 26. Hydrazine 26 is then converted to pyrazole 20 (rather thana mixture of pyrazoles 20 and 21 as in Scheme IV) by treatment with anexcess of dimethylformamide dimethyl acetal. In Scheme VI, R⁴ and R⁵ areas defined in Scheme V.

The following examples contain detailed descriptions of the methods ofpreparation of compounds of Formula I. These detailed descriptions fallwithin the scope, and serve to exemplify, the above described GeneralSynthetic Procedures which form part of the invention. These detaileddescriptions are presented for illustrative purposes only and are notintended as a restriction on the scope of the invention. All parts areby weight and temperatures are in Degrees centigrade unless otherwiseindicated. All compounds showed NMR spectra consistent with theirassigned structures. In some cases, the assigned structures wereconfirmed by nuclear Overhauser effect (NOE) experiments.

The following abbreviations are used:

HCl—hydrochloric acid

MgSO₄—magnesium sulfate

Na₂SO₄—sodium sulfate

NaIO₄—sodium periodate

NaHSO₃—sodium bisulfite

NaOH—sodium hydroxide

KOH—potassium hydroxide

P₂O₅—phosphorus pentoxide

MeOH—methanol

EtOH—ethanol

HOAc (or AcOH)—acetic acid

EtOAc—ethyl acetate

H₂O—water

H₂O₂2—hydrogen peroxide

CH₂Cl₂—methylene chloride

NaOMe—sodium methoxide

h—hour

hr—hour

min—minutes

THF—tetrahydrofuran

TLC—thin layer chromatography

DSC—differential scanning calorimetry

b.p.—boiling point

m.p.—melting point

eq—equivalent

EXAMPLE 1

4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine

Step 1: Preparation of 3-phenyl-4-(4-pyridyl)-3-butene-2-one3-Phenyl-4-(4-pyridyl)-3-butene-2-one was prepared by the method ofReichert and Lechner, Arzneim.-Forsch. 15, 36 (1965), which isincorporated by reference herein.

Step 2: Preparation of 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone

To a stirred solution of 3-phenyl-4-(4-pyridyl)-3-butene-2-one (step 1)(500 mg, 2.24 mmol) in methanol (10 ml) at room temperature was added anaqueous solution (9 ml) of sodium hydroxide (100 mg, 2.24 mmol) andhydrogen peroxide (0.5 ml of 30% aqueous solution, 4.4 mmol). Afterstirring for 2 hours, sodium chloride was added and the reaction wasextracted with ethyl acetate. The combined organic layers were driedover magnesium sulfate, filtered, and concentrated in vacuo to providethe crude 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone (385 mg, 65%) asan oil. This was used in the next step without further purification.

Step 3: Preparation of 4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine

A solution of 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone (step 2) (350mg, 1.46 mmol) and anhydrous hydrazine (0.7 ml, 20 mmol) in ethanol (3ml) was heated at reflux for 4 hours. The reaction was cooled, and thesolvent was evaporated to dryness. The resulting residue was purified bychromatography (silica gel, 1:1 acetone/hexane) to give the desiredproduct as a crystalline solid, which was recrystallized from ethylacetate and hexane to give pure4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine (145 mg, 42%): m. p.164-165° C. Anal. Calc'd for C₁₅H₁₃N₃ (235.29): C, 76.57; H, 5.57; N,17.86. Found: C, 76.49; H, 5.45; N, 17.70.

The compounds of Examples 2 through 8 were synthesized in accordancewith the chemistry described above (particularly in Scheme III) byselection of the corresponding starting reagents:

EXAMPLE 2

4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine

The cyanoketone 1 of Scheme III wherein X is p-fluoro was synthesizedaccording to the procedure of I. Lantos et al., J. Org. Chem., 53,4223-4227 (1988), which is incorporated herein by reference. A solutionof the cyanoketone (10 g, 41 mmol), hydrazine hydrate (2.5 ml) andacetic acid (5.2 ml) in benzene (100 ml) was refluxed for 4 hours. Thereaction was cooled and extracted with 3N HCl. The combined acidextracts were basified to pH 10 using concentrated ammonium hydroxidewith cooling. The basic aqueous layer was extracted with methylenechloride and the combined organic extracts were dried over magnesiumsulfate.

The drying agent was filtered and the filtrate concentrated in vacuo togive the crude 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-aminewhich was purified by recrystallization from ethyl acetate and hexane.Purified 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine had m.p.178-180° C. (capillary).

Anal. Calc'd for C₁₄H₁₁N₄F+0.25 H₂O: C, 64.99; H, 4.48; N, 21.65. Found:C, 64.99; H, 4.48; N, 21.54.

EXAMPLE 3

N-[4 (4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide

A solution of 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amineprepared as set forth in Example 2 (200 mg, 0.77 mmol) andmethanesulfonyl chloride (90 mg) in pyridine (5 ml) was stirred at roomtemperature overnight. The pyridine was removed in vacuo and the residuewas treated with methylene chloride and water. The resultant precipitatewas filtered to giveN-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide.AdditionalN-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamidewas contained in the methylene chloride layer. The methylene chloridewas stripped in vacuo and the residue purified by chromatography onsilica gel using mixtures of ethyl acetate and methanol as eluents. ThepurifiedN-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamidehad m.p. 168-170° C.

Anal. Calc'd for C₁₅H₁₃N₄SO₂F+0.25 H₂O: C, 53.48; H, 4.04; N, 16.63.Found: C, 53.41; H, 3.78; N, 16.52.

EXAMPLE 4

N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylsulfamide

Methyl sulfamyl chloride was synthesized by refluxing a solution ofmethylsulfamic acid (1.0 g) in phosphorus oxychloride (10 mL) for 6hours. The excess phosphorus oxychloride was removed in vacuo and theresidual oil was used for the synthesis of the product without furthertreatment. A solution of4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as setforth in Example 2 (200 mg, 0.77 mmol) and approximately 1 mmol of theabove oil in pyridine (5 ml) was stirred at room temperature for 2hours. The reaction was stripped in vacuo and the residue purified bychromatography on silica gel using ethyl acetate and mixtures of ethylacetate and methanol as eluents to giveN-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-1-yl]-N′-methylsulfamideas a crystalline solid, m. p. 194-195° C.

Anal. Calc'd for C₁₅H₁₄N₅SO₂F+1.0 H₂O: C, 49.31; H, 4.41; N, 19.17.Found: C, 49.13; H, 3.97; N, 19.01.

EXAMPLE 5

[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]urea

A suspension of 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amineprepared as set forth in Example 2 (200 mg, 0.77 mmol) in a solution ofdi-tert-butyl carbonate (185 mg, 0.9 mmol) and 4-dimethylaminopyridine(DMAP) (10 mg) in methylene chloride (10 ml) was stirred at roomtemperature for 20 minutes, during which time, the suspended materialdissolved. N-Propylamine (50 mg) was added and stirring was continued atroom temperature for 1 hour. The reaction was then refluxed for 15minutes, cooled and stripped in vacuo. Treatment with ethyl acetate andhexane resulted in the deposition of crystals of the tert-butoxycarbonylderivative, m.p. 183-184° C.

Anal. Calc'd for C₁₉H₁₉N₄O₂F: C, 64.40; H, 5.40; N, 15.81. Found: C,64.66; H, 5.63; N, 15.63.

A solution of the tert-butoxycarbonyl derivative above (100 mg, 0.3mmol) in tetrahydrofuran was treated with ammonia at 80° C. in apressure bottle for 12 hours. The reaction was stripped in vacuo and theresidue was purified by chromatography on silica gel eluting withmixtures of ethyl acetate and methanol. The purified[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]urea thus obtainedhad m.p. 224-225° C.

Anal. Calc'd for C₁₅H₁₂N₅O: C, 60.60; H, 4.07; N, 23.56. Found: C,60.21; H, 4.11; N, 23.30.

EXAMPLE 6

[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]sulfamide

Sulfamyl chloride was synthesized from chlorosulfonyl isocyanateaccording to the procedure described by R. Graf in Chemische Berichte,p. 509 (1959), which is incorporated herein by reference. A solution of4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as setforth in Example 2 (200 mg, 0.77 mmol), sulfamyl chloride (100 mg, 0.8mmol) and triethylamine (200 mg, 2 mmol) in benzene (5 ml) andacetonitrile (5 ml) was stirred at room temperature for 2 hours. Thereaction was stripped in vacuo and residue was treated with water andbasified to pH 7 with ammonium hydroxide. The resultant precipitate waspurified by chromatography on silica gel using mixtures of ethyl acetateand methanol as eluents. The purified[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]sulfamide thusobtained had m.p. 201-202° C.

Anal. Calc'd for C₁₄H₁₂N₅SO₂F: C, 50.44; H, 3.63; N, 21.01. Found: C,50.43; H, 3.45; N, 20.89.

EXAMPLE 7

4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazol-5-amine

A solution of cyanoketone 1 of Scheme III wherein X is p-chloro (1.5 g,5.19 mmol), methylhydrazine (0.35 ml) and acetic acid (0.75 ml) inbenzene (15 ml) was refluxed for 3.5 hours. The reaction was cooled andextracted with 3N HCl. The aqueous layer was concentrated on the rotaryevaporator and then basified with ammonium hydroxide. The resultantprecipitate was recrystallized from methanol to give pure4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazol-5-amine, m.p.257-258° C.

Anal. Calc'd for C₁₅H₁₃N₄Cl: C, 63.27; H, 4.60; N, 19.68. Found: C,62.93; H, 4.45; N, 19.64.

EXAMPLE 8

N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylurea

A solution of 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amineprepared as set forth in Example 2 (100 mg, 0.38 mmol), methylisocyanate (22 mg, 0.39 mmol) and 4-dimethylaminopyridine (2.5 mg) inmethylene chloride (10 ml) was stirred at room temperature for 30minutes. The reaction was stripped in vacuo. The residue was trituratedwith hexane and the solid filtered to give pureN-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylurea, m.p. 212-213° C.

Anal. Calc'd for C₁₆H₁₄N₅FO: C, 61.73; H, 4.53; N, 22.50. Found: C,61.63; H, 4.55; N, 22.47.

The compounds of Examples 9 through 11 were synthesized in accordancewith the chemistry described above (particularly in Scheme IV) byselection of the corresponding starting reagents:

EXAMPLE 9

4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine

Step 1

Methyl isonicotinate (13.7 g, 0.1 mole) and ethyl 4-fluorophenylacetate(18.2 g, 0.1 mole) were mixed together, then sodium methoxide (8.1 g,0.15 mole) was added. The mixture was heated to 60-70° C. for 24 hourswhile nitrogen was blown through the flask to eliminate methanol.Concentrated hydrochloric acid (50 mL) then was added and the reactionmixture was refluxed for 3 hours. After addition of water (30 mL), thereaction mixture was extracted with chloroform, and the water phase wasneutralized to pH 6-7 with aqueous sodium hydroxide (1M). Theprecipitate formed was collected by filtration, washed with water anddried under vacuum to give 10 g of2-(4-fluorophenyl)-1-(4′-pyridyl)-ethan-1-one (yield: 46%). ¹H NMR:consistent with the assigned structure and/or its tautomer.

Step 2

2-(4-fluorophenyl)-1-(4′-pyridyl)-ethan-1-one prepared above (1 g) wasdissolved in 50 mL tetrahydrofuran and N,N-dimethylformamide dimethylacetal (5 mL) was added. The mixture was stirred at room temperature for2 days. After evaporating the solvent, the solid obtained was washedwith hexane and 1 g of the vinyl amine was obtained. This vinyl amine(0.5 g) was dissolved in ethanol (15 mL) and hydrazine hydrate (5 mL)was added. The mixture was stirred at 0° C. for 2 hours and thenevaporated to dryness. After recrystallization from methanol/water, 400mg of 4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine was obtained in 91%yield. MS, 240(M+1); ¹H NMR: consistent with the assigned structure;Anal. Calc'd for C₁₄H₁₀FN₃.0.2H₂O: C, 69.24; H, 4.32; N, 17.30. Found:C, 69.54; H, 4.06; N, 17.43.

EXAMPLE 10

4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine

When methylhydrazine was substituted for hydrazine hydrate in Step 2 ofExample 9, 4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine (theN-methyl derivative corresponding to the compound of Example 9) wasobtained. Purification by recrystallization from toluene and hexane givethe pure 4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine in 57%yield. MS m/z: 254 (M+1). ¹H NMR: consistent with the assignedstructure. Anal. calc'd for C₁₅H₁₂FN₃: C, 71.13; H, 4.78; N, 16.69.Found: C, 70.99; H, 4.68; N, 16.65.

EXAMPLE 11

4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol and4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazole-1-ethanol

The procedure set forth in Example 9 was followed except that2-hydroxyethyl hydrazine was substituted for hydrazine hydrate.4-(4-Fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol and4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazole-1-ethanol were obtainedas a mixture by recrystallization from toluene and hexane in 67% yield.¹H NMR: consistent with the assigned structure. Mass spectrum, m/z: 284(M+1). Anal. calc'd for C₁₆H₁₄FN₃O: C, 67.83; H, 4.98; N, 14.83. Found:C, 67.86; H, 5.04; N. 14.85.

The compounds of Examples 12 and 13 were synthesized in accordance withthe chemistry described above (particularly in Scheme V) by selection ofthe corresponding starting reagents:

EXAMPLE 12

4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamineand4-(4fluorophenyl)-N,N-dimethyl-5-(4-pyridinyl)-1H-pyrazole-1-ethanamine

4-(4-Fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol (or4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazole-1-ethanol) prepared asset forth in Example 11 (1.36 g) was dissolved in 30 mL pyridine andcooled to 0° C., whereupon methanesulfonyl chloride (0.6 mL) was added.After stirring at 0° C. for 12 hours, about 20 g of ice was added, andthe mixture was extracted with toluene (300 ml). After evaporation, theresidue was used directly without further purification. 0.7 g of theabove obtained compound was dissolved in methanol (25 mL), anddimethylamine/THF solution (4M, 2 mL) was added. The reaction on mixturewas refluxed for 12 hours, then evaporated to dryness. The residue waspurified by chromatography (methanol/dichloromethane 1:10). A mixture(0.59 g) of4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamineand4-(4-fluorophenyl)-N,N-dimethyl-5-(4-pyridinyl)-1H-pyrazole-1-ethanaminewere obtained. ¹H NMR: consistent with the assigned structure. Massspectrum, m/z: 311 (M+1). Anal. calc'd C₁₈H₁₉N₄F.0.55H₂O: C, 67.50; H,6.33; N, 17.49. Found: C, 67.21; H, 6.46; N, 17.14.

EXAMPLE 13

4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholineand4-[2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine

The procedure set forth in Example 11 was followed, except thatmorpholine was substituted for dimethylamine, to produce a mixture of4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholineand4-[2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine.Mass spectrum, m/z: 353 (M+1). Anal. calc'd for C₂₀H₂₁N₄OF+0.5H₂O: C,66.47; H, 6.14; N, 15.50. Found: C, 66.57; H, 6.27; N. 15.14.

The compound of Example 14 was synthesized in accordance with thechemistry described above (particularly in Scheme VI) by selection ofthe corresponding starting reagents:

EXAMPLE 14

4-[4-(4--fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine

2-(4-fluorophenyl)-1-(4′-pyridyl)-ethan-1-one prepared as set forth instep 1 of Example 9 (0.5 g, 0.00232 moles) was mixed with of 98% methylhydrazine (0.2 g, 0.00462 moles) in 10 mL of ethanol containing 0.1 mLof acetic acid in a 50 mL Erlenmeyer flask. After gentle boiling (30minutes on a steam bath) a small sample was evacuated at high vacuum andexamined by NMR to confirm completion of hydrazone formation. Thereaction mixture was concentrated to a pasty mass and 3.6 mL of DMFdimethylacetal (0.027 moles) was then added and heated to 80° C. for 30minutes, at which point a clear yellow viscous solution was obtained.The reaction was checked for completion (TLC or NMR) and concentratedand taken up in 20 mL of chloroform. After washing with water (10 mL),the organic layer was extracted with 15 mL of 10% HCl. The water layerwas then treated with 0.5 g of activated charcoal at 70° C. for 10minutes, filtered through celite, neutralized cautiously to pH 7-8 withvigorous stirring and cooling. The fine off-white precipitate wasfiltered and dried. NMR was found to be in agreement with the proposedstructure. The precipitate,4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine, obtained inquantitative yield was filtered, washed with ether and dried. Yield:0.45 g (77%). Mass spectrum, m/z: 254. Anal. calc'd: C, 62.18; H, 4.52;N. 14.50. Found: C, 62.39; H, 4.07; N, 14.24.

EXAMPLE 15

4-[4-(4-chlorcophenyl)-1H-pyrazol-3-yl]pyridine

4-[4-(4-chlorcphenyl)-1H-pyrazol-3-yl]pyridine was prepared according tothe procedure set forth in Example 9 except that ethyl4-chlorophenylacetate was substituted for ethyl 4-fluorophenylacetate;m.p. 204-207° C.

Anal. Calc'd: C, 65.76; H, 3.94; N, 16.43. Found: C, 65.44; H, 3.78; N,16.04.

EXAMPLE 16

4-(4-phenyl-1H-pyrazol-5-yl)pyridine

4-(4-phenyl-1H-pyrazol-5-yl)pyridine can be prepared in accordance withthe procedure set forth in Example 9 by substituting ethylphenylacetatefor ethyl 4-fluorophenylacetate.

EXAMPLE 17

1-methyl-4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]]piperidineand1-methyl-4-[2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-1-yl]piperidine

This compound can be prepared using the procedure sea forth for thesynthesis of the compound of Example 11 by substituting4-hydrazino-N-methylpiperidine for hydroxyethyl hydrazine.4-Hydrazino-N-methylpiperidine is synthesized as disclosed in Ebnoetheret al, Helv. Chim. Acta (1959) 42, 533, 541, 560. The resulting mixtureis separated into the respective pure title compounds by chromatographyon silica gel, eluting with methanol/dichloromethane (1:10), or othersuitable solvent system.

BIOLOGICAL EVALUATION

p38 Kinase Assay

Cloning of Human p38a

The coding region of the human p38a cDNA was obtained byPCR-amplification from RNA isolated from the human monocyte cell lineTHP.1. First strand cDNA was synthesized from total RNA as follows: 2 μgof RNA was annealed to 100 ng of random hexamer primers in a 10 μlreaction by heating to 70° C. for 10 minutes followed by 2 minutes onice. cDNA was then synthesized by adding 1 μl of RNAsin (Promega,Madison Wis.), 2 μl of 50 mM dNTP's, 4 μl of 5× buffer, 2 μl of 100 mMDTT and 1 μl (200 U) of Superscript II™ AMV reverse transcriptase.Random primer, dNTP's and Superscript™ reagents were all purchased fromLife-Technologies, Gaithersburg, Mass. The reaction was incubated at 42°C. for 1 hour. Amplification of p38 cDNA was performed by aliquoting 5μl of the reverse transcriptase reaction into a 100 μl PCR reactioncontaining the following: 80 μl dH₂O, 2 μl 50 mM dNTP's, 1 μl each offorward and reverse primers (50 pmol/μl), 10 μl of 10× buffer and 1 μlExpand™ polymerase (Boehringer Mannheim). The PCR primers incorporatedBam HI sites onto the 5′ and 3′ end of the amplified fragment, and werepurchased from Genosys. The sequences of the forward and reverse primerswere 5′-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3′ and5′GATCGAGGATTCTCAGGACTCCATCTCTTC-3′ respectively. The PCR amplificationwas carried out in a DNA Thermal Cycler (Perkin Elmer) by repeating 30cycles of 94° C. for 1 minute, 60° C. for 1 minute and 68° C. for 2minutes. After amplification, excess primers and unincorporated dNTP'swere removed from the amplified fragment with a Wizard™ PCR prep(Promega) and digested with Bam HI (New England Biolabs). The Bam HIdigested fragment was ligated into BamHI digested pGEX 2T plasmid DNA(PharmaciaBiotech) using T-4 DNA ligase (New England Biolabs) asdescribed by T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nded. (1989). The ligation reaction was transformed into chemicallycompetent E. coli DH10B cells purchased from Life-Technologies followingthe manufacturer's instructions. Plasmid DNA was isolated from theresulting bacterial colonies using a Promega Wizard™ miniprep kit.Plasmids containing the appropriate Bam HI fragment were sequenced in aDNA Thermal Cycler (Perkin Elmer) with Prism™ (Applied Biosystems Inc.).cDNA clones were identified that coded for both human p38a isoforms (Leeet al. Nature 372, 739). One of the clones which contained the cDNA forp38a-2 (CSBP-2) inserted in the cloning site of pGEX 2T, 3′ of the GSTcoding region was designated pMON 35802. The sequence obtained for thisclone is an exact match of the CDNA clone reported by Lee et al. Thisexpression plasmid allows for the production of a GST-p38a fusionprotein.

Expression of Human p38a

GST/p38a fusion protein was expressed from the plasmid pMON 35802 in E.coli, stain DH10B (Life Technologies, Gibco-BRL). Overnight cultureswere grown in Luria Broth (LB) containing 100 mg/ml ampicillin. The nextday, 500 ml of fresh LB was inoculated with 10 ml of overnight culture,and grown in a 2 liter flask at 37° C. with constant shaking until theculture reached an absorbance of 0.8 at 600 nm. Expression of the fusionprotein was induced by addition of isopropyl b-D-thiogalactosidse (IPTG)to a final concentration of 0.05 mM. The cultures were shaken for threehours at room temperature, and the cells were harvested bycentrifugation. The cell pellets were stored frozen until proteinpurification.

Purification of p38 Kinase-α

All chemicals were from Sigma Chemical Co. unless noted. Twenty grams ofE. coli cell pellet collected from five 1 L shake flask fermentationswas resuspended in a volume of PBS (140 mM NaCl, 2.7 mM KCl, 10 mMNa₂HPO₄, 1.8 MM KH₂PO₄, pH 7.3) up to 200 ml. The cell suspension wasadjusted to 5 mM DTT with 2 M DTT and then split equally into five 50 mlFalcon conical tubes. The cells were sonnicated (Ultrasonics model W375)with a 1 cm probe for 3×1 minutes (pulsed) on ice. Lysed cell materialwas removed by centrifugation (12,000×g, 15 minutes) and the clarifiedsupernatant applied to glutathione-senharose resin (Pharmacia).

Glutathione-Secharose Affinity Chromatography

Twelve ml of a 50% glutathione sepharose-PBS suspension was added to 200ml clarified supernatant and incubated batchwise for 30 minutes at roomtemperature. The resin was collected by centrifugation (600×g, 5 min)and washed with 2×150 ml PBS/1% Triton X-100, followed by 4×40 ml PBS.To cleave the p38 kinase from the GST-p38 fusion protein, theglutathione-sepharose resin was resuspended in 6 ml PBS containing 250units thrombin protease (Pharmacia, specific activity>7500 units/mg) andmixed gently for 4 hours at room temperature. The glutathione-sepharoseresin was removed by centrifugation (600×g, 5 min) and washed 2×6 mlwith PBS. The PBS wash fractions and digest supernatant containing p38kinase protein were pooled and adjusted to 0.3 mM PMSF.

Mono Q Anion Exchange Chromatography

The thrombin-cleaved p38 kinase was further purified by FPLC-anionexchange chromatography. Thrombin-cleaved sample was diluted 2-fold withBuffer A (25 mM HEPES, pH 7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5%glycerol) and injected onto a Mono Q HR 10/10 (Pharmacia) anion exchangecolumn equilibrated with Buffer A. The column was eluted with a 160 ml0.1 M-0.6 M NaCl/Buffer A gradient (2 ml/minute flowrate). The p38kinase peak eluting at 200 mM NaCl was collected and concentrated to 3-4ml with a Filtron 10 concentrator (Filtron Corp.).

Sephacryl S100 Gel Filtration Chromatography

The concentrated Mono Q-p38 kinase purified sample was purified by gelfiltration chromatography (Pharmacia Hiprep 26/60 Sephacryl S100 columnequilibrated with Buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT,5% glycerol)). Protein was eluted from the column with Buffer B at a 0.5ml/minute flowrate and protein was detected by absorbance at 280 nm.Fractions containing p38 kinase (detected by SDS-polyacrylamide gelelectrophoresis) were pooled and frozen at −80° C. Typical purifiedprotein yields from 5 L E. coli shake flasks fermentations were 35 mgp38 kinase.

In Vitro Assay

The ability of compounds to inhibit human p38 kinase alpha was evaluatedusing two in vitro assay methods. In the first method, activated humanp38 kinase alpha phosphorylates a biotinylated substrate, PHAS-I(phosphorylated heat and acid stable protein-insulin inducible), in thepresence of gamma ³²P-ATP (³²P-ATP). PHAS-I was biotinylated prior tothe assay and provides a means of capturing the substrate which isphosphorylated during the assay. p38 Kinase was activated by MKK6.Compounds were tested in 10 fold serial dilutions over the range of 100μM to 0.001 μM using 1% DMSO. Each concentration of inhibitor was testedin triplicate.

All reactions were carried out in 96 well polypropylene plates. Eachreaction well contained 25 mM HEPES pH 7.5, 10 mM magnesium acetate and50 μM unlabeled ATP. Activation of p38 was required to achievesufficient signal in the assay. Biotinylated PHAS-I was used at 1-2 μgper 50 μl reaction volume, with a final concentration of 1.5 μM.Activated human p38 kinase alpha was used at 1 μg per 50 μl reactionvolume representing a final concentration of 0.3 μM. Gamma ³²P-ATP wasused to follow the phosphorylation of PHAS-I. ³²P-ATP has a specificactivity of 3000 Ci/mmol and was used at 1.2 μCi per 50 μl reactionvolume. The reaction Proceeded either for one hour or overnight at 30°C.

Following incubation, 20 μl of reaction mixture was transferred to ahigh capacity streptavidin coated filter plate (SAM-streptavidin-matrix,Promega) prewetted with phosphate buffered saline. The transferredreaction mix was allowed to contact the streptavidin membrane of thePromega plate for 1-2 minutes. Following capture of biotinylated PHAS-Iwith ³²P incorporated, each well was washed to remove unincorporated³²P-ATP three times with 2M NaCl, three washes of 2M NaCl with 1%phosphoric, three washes of distilled water and finally a single wash of95% ethanol. Filter plates were air dried and 20 μl of scintillant wasadded. The plates were sealed and counted.

A second assay format was also employed that is based on p38 kinasealpha induced phosphorylation of EGFRP (epidermal growth factor receptorpeptide, a 21 mer) in the presence of ³³P-ATP. Compounds were tested in10 fold serial dilutions over the range of 100 μM to 0.001 μM in 1%DMSO. Each concentration of inhibitor was tested in triplicate.Compounds were evaluated in 50 μl reaction volumes in the presence of 25mM Hepes pH 7.5, 10 mM magnesium acetate, 4% glycerol, 0.4% bovine serumalbumin, 0.4 mM DTT, 50 μM unlabeled ATP, 25 μg EGFRP (200 μM), and 0.05uCi gamma ³³P-ATP. Reactions were initiated by addition of 0.09 μg ofactivated, purified human GST-p38 kinase alpha. Activation was carriedout using GST-MKK6 (5:1,p38:MKK6) for one hour at 30° C. in the presenceof 50 μM ATP. Following incubation for 60 minutes at room temperature,the reaction was stopped by addition of 150 μl of AG 1×8 resin in 900 mMsodium formate buffer, pH 3.0 (1 volume resin to 2 volumes buffer). Themixture was mixed three times with pipetting and the resin was allowedto settle. A total of 50 μl of clarified solution head volume wastransferred from the reaction wells to Microlite-2 plates. 150 μl ofMicroscint 40 was then added to each well of the Microlite plate, andthe plate was sealed, mixed, and counted.

TNF Cell Assays

Method of Isolation of Human Peripheral Blood Mononuclear Cells

Human whole blood was collected in Vacutainer tubes containing EDTA asan anticoagulant. A blood sample (7 ml) was carefully layered over 5 mlPMN Cell Isolation Medium (Robbins Scientific) in a 15 ml round bottomcentrifuge tube. The sample was centrifuged at 450-500×g for 30-35minutes in a swing out rotor at room temperature. After centrifugation,the top band of cells were removed and washed 3 times with PBS w/ocalcium or magnesium. The cells were centrifuged at 400×g for 10 minutesat room temperature. The cells were resuspended in Macrophage Serum FreeMedium (Gibco BRL) at a concentration of 2 million cells/ml.

LPS Stimulation of Human PBMs

PBM cells (0.1 ml, 2 million/ml) were co-incubated with 0.1 ml compound(10-0.41 μM, final concentration) for 1 hour in flat bottom 96 wellmicrotiter plates. Compounds were dissolved in DMSO initially anddiluted in TCM for a final concentration of 0.1% DMSO. LPS (Calbiochem,20 ng/ml, final concentration) was then added at a volume of 0.010 ml.Cultures were incubated overnight at 37° C. Supernatants were thenremoved and tested by ELISA for TNF-a and IL1-b. Viability was analyzedusing MTS. After 0.1 ml supernatant was collected, 0.020 ml MTS wasadded to remaining 0.1 ml cells. The cells were incubated at 37° C. for2-4 hours, then the O.D. was measured at 490-650 nM.

Maintenance and Differentiation of the U937 Human Histiocytic LymphomaCell Line

U937 cells (ATCC) were propagated in RPMI 1640 containing 10% Fetalbovine serum, 100 IU/ml penicillin, 100 μg/ml streptomycin, and 2 mMglutamine (Gibco). Fifty million cells in 100 ml media were induced toterminal monocytic differentiation by 24 hour incubation with 20 ng/mlphorbol 12-myristate 13-acetate (Sigma). The cells were washed bycentrifugation (200×g for 5 min) and resuspended in 100 ml fresh medium.After 24-48 hours, the cells were harvested, centrifuged, andresuspended in culture medium at 2 million cells/ml.

LPS Stimulation of TNF production by U937 Cells

U937 cells (0.1 ml, 2 million/ml) were incubated with 0.1 ml compound(0.004-50 μM, final concentration) for 1 hour in 96 well microtiterplates. Compounds were prepared as 10 mM stock solutions in DMSO anddiluted in culture medium to yield a final DMSO concentration of 0.1% inthe cell assay. LPS (E. coli, 100 ng/ml final concentration) was thenadded at a volume of 0.02 ml. After 4 hour incubation at 37° C., theamount of TNF-α released in the culture medium was quantitated by ELISA.Inhibitory potency is expressed as IC50 (μM).

Rat Assay

The efficacy of the novel compounds in blocking the production of TNFalso was evaluated using a model based on rats challenged with LPS. MaleHarlen Lewis rats [Sprague Dawley Co.] were used in this model. Each ratweighed approximately 300 g and was fasted overnight prior to testing.Compound administration was typically by oral gavage (althoughintraperitoneal, subcutaneous and intravenous administration were alsoused in a few instances) 1 to 24 hours prior to the LPS challenge. Ratswere administered 30 μg/kg LPS [salmonella typhosa, Sigma Co.]intravenously via the tail vein. Blood was collected via heart puncture1 hour after the LPS challenge. Serum samples were stored at −20° C.until quantitative analysis of TNF-α by Enzyme Linked-Immuno-SorbentAssay (“ELISA”) [Biosource]. Additional details of the assay are setforth in Perretti, M., et al., Br. J. Pharmacol. (1993), 110, 868-874,which is incorporated by reference in this application.

Mouse Assay

Mouse Model Of LPS-Induced TNF Aloha Production

TNF alpha was induced in 10-12 week old BALB/c female mice by tail veininjection with 100 ng lipopolysaccharide (from S. Typhosa) in 0.2 mlsaline. One hour later mice were bled from the retroorbital sinus andTNF concentrations in serum from clotted blood were quantified by ELISA.Typically, peak levels of serum TNF ranged from 2-6 ng/ml one hour afterLPS injection.

The compounds tested were administered to fasted mice by oral gavage asa suspension in 0.2 ml of 0.5% methylcellulose and 0.025% Tween 20 inwater at 1 hour or 6 hours prior to LPS injection. The 1 hour protocolallowed evaluation of compound potency at Cmax plasma levels whereas the6 hour protocol allowed estimation of compound duration of action.Efficacy was determined at each time point as percent inhibition ofserum TNF levels relative to LPS injected mice that received vehicleonly.

Induction And Assessment Of Collagen-Induced Arthritis In Mice

Arthritis was induced in mice according to the procedure set forth in J.M. Stuart, Collagen Autoimmune Arthritis, Annual Rev. Immunol. 2:199(1984), which is incorporated herein by reference. Specifically,arthritis was induced in 8-12 week old DBA/1 male mice by injection of50 μg of chick type II collagen (CII) (provided by Dr. Marie Griffiths,Univ. of Utah, Salt Lake City, Utah) in complete Freund's adjuvant(Sigma) on day 0 at the base of the tail. Injection volume was 100 μl.Animals were boosted on day 21 with 50 μg of CII in incomplete Freund'sadjuvant (100 μl volume). Animals were evaluated several times each weekfor signs of arthritis. Any animal with paw redness or swelling wascounted as arthritic. Scoring of arthritic paws was conducted inaccordance with the procedure set forth in Wooley et al., GeneticControl of Type II Collagen Induced Arthritis in Mice: FactorsInfluencing Disease Suspectibility and Evidence for Multiple MHCAssociated Gene Control., Trans. Proc., 15:180 (1983). Scoring ofseverity was carried out using a score of 1-3 for each paw (maximalscore of 12/mouse). Animals displaying any redness or swelling of digitsor the paw were scored as 1. Gross swelling of the whole paw ordeformity was scored as 2. Ankylosis of joints was scored as 3. Animalswere evaluated for 8 weeks. 8-10 animals per group were used.

Preparation And Administration Of Compounds

The compounds tested on mice having collagen-induced arthritis wereprepared as a suspension in 0.5% methylcelluose (Sigma, St. Louis, Mo.),0.025% Tween 20 (Sigma). The compound suspensions were administered byoral gavage in a volume of 0.1 ml b.i.d. Administration began on day 20post collagen injection and continued daily until final evaluation onday 56. Scoring of arthritic paws was conducted as set forth above.

Results obtained using the above-described assays are set, forth inTable I below. p38 assay and U937 cell assay results are expressed asIC₅₀ (μm). Mouse-LPS assay results are expressed as percent inhibition.

TABLE I mLPS P38α¹ p38α² U937 (6 h @ Example (μM) (μM) (μM) (30 mpk) 130.00 13.35 10.00 2 6.21 10.61 3 2.55 >10.00 4 0.23 4.70 54 5 1.98 5.536 10.00 7 5.48 10.00 8 10.00 9 2.44 3.46 0.6474 42 10 7.23 0.4 1.5987 7611 0.695 10 40 12 0.941 10 −5 13 0.86 >10 22 15 5.9 0.75 32 ¹p38α invitro results based on PHAS-I assay procedure ²p38α in vitro resultsbased on EGFRP assay procedure

Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of this invention inassociation with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The active compounds andcomposition may, for example, be administered orally, intravascularly(IV), intraperitoneally, subcutaneously, intramuscularly (IM) ortopically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, hard or soft capsule, lozenges,dispensable powders, suspension or liquid. The pharmaceuticalcomposition is preferably made in the form of a dosage unit containing aparticular amount of the active ingredient. Examples of such dosageunits are tablets or capsules. The active ingredient may also beadministered by injection (IV, IM, subcutaneous or jet) as a compositionwherein, for example, saline, dextrose, or water may be used as asuitable carrier. The pH of the composition may be adjusted, ifnecessary, with suitable acid, base, or buffer. Suitable bulking,dispersing, wetting or suspending agents, including mannitol and PEG400, may also be included in the composition. A suitable parenteralcomposition can also include a compound formulated as a sterile solidsubstance, including lyophilized powder, in injection vials. Aqueoussolution can be added to dissolve the compound prior to injection. Theamount of therapeutically active compounds that are administered and thedosage regimen for treating a disease condition with the compoundsand/or compositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, theseverity of the inflammation or inflammation related disorder, the routeand frequency of administration, and the particular compound employed,and thus may vary widely. The pharmaceutical compositions may containactive ingredients in the range of about 0.1 to 1000 mg, preferably inthe range of about 7.0 to 350 mg. A daily dose of about 0.01 to 100mg/kg body weight, preferably between about 0.1 and about 50 mg/kg bodyweight and most preferably between about 0.5 to 30 mg/kg body weight,may be appropriate. The daily dose can be administered in one to fourdoses per day. In the case of skin conditions, it may be preferable toapply a topical preparation of compounds of this invention to theaffected area two to four times a day. For disorders of the eye or otherexternal tissues, e.g., mouth and skin, the formulations are preferablyapplied as a topical gel, spray, ointment or cream, or as a suppository,containing the active ingredients in a total amount of, for example,0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to15% w/w. When formulated in an ointment, the active ingredients may beemployed with either paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane. The transdermal patch may include the compound in a suitablesolvent system with an adhesive system, such as an acrylic emulsion, anda polyester patch. The oily phase of the emulsions of this invention maybe constituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others. The choice of suitable oils or fats for the formulation isbased on achieving the desired cosmetic properties, since the solubilityof the active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The antiinflammatory active ingredients are preferablypresent in such formulations in a concentration of 0.5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w. Fortherapeutic purposes, the active compounds of this combination inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

All patent documents listed herein are incorporated by reference.Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

What is claimed is:
 1. A compound, a tautomer of the compound, or apharmaceutically-acceptable salt of the compound or tautomer, wherein:the compound corresponds in structure to Formula I:

 R¹ is hydroxyalkyl; R² is selected from the group consisting ofhydrido, alkyl, alkenyl, alkynyl, heterocyclyl, haloalkyl,heterocyclylalkelene, amino, alkylamino, aminoalkyl, alkoxy, alkylthio,carboxy, alkoxycarbonyl, carboxyalkyl, aminocarbonylamino,alkylamicarbonylamino, alkysulfonyl, aminosulfonyl, alkylsulfonylamino,amisosulfonylamino, alkylaminosulfonylamino, and alkynylamino, wherein:the heterocyclyl and heterocyclylalkelene are optionally substitutedwith one or more radicals independently selected from the groupconsisting of alkylthio, alkylsulfonyl, alkylsulfinyl, halo, alkyl,alkoxy, aryloxy, aralkoxy, heterocyclyl, haloalkyl, amino, cyano, andhydroxy; Ar¹ is aryl optionally substituted with one or more radicalsindependently selected from the group consisting of halo, alkyl, alkenylalkynyl, alkoxy, alkenoxy, alkyldioxy, alkylthio, alkylsulfinyl,alkylsulfonyl, amino, aminocarbonyl, cyano, alkoxycarbonyl, formyl,aminosulfonyl, alkylamino, nitro, arylamino, arlkylcarbonylamino,halosulfonyl, aminoalkyl, and haloalkyl; HetAr² is selected from thegroup consisting of pyridinyl, and quinolinyl, wherein: the pyridinyl,pyrimidinyl, and quinolinyl are optionally substituted with one or moreradicals independently selected from the group consisting of alkylthio,alkylsulfonyl, alkylsulfinyl, halo, alkyl, heterocyclcyl, alkoxy,aralkoxy, haloalkyl, amino, cyano, aralkyl, alkylamino, cycloalkylamino,cycloalkenylamino, arylamino, alkynylamino, and aralkylamino; and ifHetAr² is pyridinyl, then R² is selected from the group consisting ofhydrido, alkyl, alkenyl, alkynyl, haloalkyl, heterocyclylalkelene,aminoalkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl, carboxyalkyl,aminocarbonylamino, alkylaminocarbonylamino, alkylsulfonyl,aminosulfonyl, alkylsulfonylamino, aminosulfonylamino,alkylaminosulfonylamino, and alkynylamino, wherein: Theheterocyclylalkelene is optionally substituted with one or more radicalsindependently selected from the group consisting of alkylthio,alkylsulfonyl, alkylsulfinyl, halo, alkyl, alkoxy, aryloxy, aralkoxy,heterocyclyl, haloalkyl, amino, cyano, and hydroxy.
 2. A compound, salt,or tautomer of claim 1, wherein: R¹ is lower hydroxyalkyl; R² isselected from the group consisting of hydrido, lower alkyl, loweralkenyl, lower alkynyl, lower haloalkyl, lower heterocyclyl, lowerheterocyclylalkylene, amino, lower alkylamino, lower alkynylamino, loweraminoalkyl, lower alkylthio, lower carboxy, lower alkoxycarbonyl, lowercarboxyalkyl, lower aminocarbonylamino, lower alkylaminocarbonylamino,lower alkylsulfonyl, lower aminosulfonyl, lower alkylsulfonylamino,lower aminosulfonylamino, and lower alkylaminosulfonylamino, wherein:the heterocyclyl and heterocyclylalkelene are optionally ubstituted withone or more radicals independently selected from the group consisting oflower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, halo, loweralkyl, lower alkoxy, aryloxy, lower heterocyclyl, lower haloalkyl,amino, and cyano; Ar¹ is selected from the group consisting of phenyl,biphenyl, and naphthyl, wherein: the phenyl, biphenyl, and naphthyl areoptionally substituted with one or more radicals independently selectedfrom the group consisting of lower alkylthio, lower alkylsulfonyl,aminosulfonyl, halo, lower alkyl, lower alkenyl, lower alkynyl, loweralkylsulfinyl, cyano, lower alkoxycarbonyl, aminocarbonyl, formyl, loweralkylcarbonylamino, lower haloalkyl, lower alkoxy, lower alkenyloxy,lower alkyldioxy, amino, lower alkylamino, lower aminoalkyl, arylamino,nitro, and halosulfonyl; and HetAr² is selected from the groupconsisting of pyridinyl and pyrimidinyl, wherein: the pyridinyl andpyrimidinyl are optionally substituted with one or more radicalsindependently selected from the group consisting of lower alkylthio,lower alkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, lowerheterocyclyl, lower alkoxy, lower aralkoxy, lower haloalkyl, amino,cyano, lower aralkyl, lower alkylamino, lower cycloalkylamino, lowerarylamino, lower ailcynylamino, and lower aralkylamino.
 3. A compound,salt, or tautomer of claim 2, wherein: R² is selected from the groupconsisting of hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl,isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichioromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl, dichloropropyl, amino, N-methylamino,N,N-dimethylamino, ethynylamino, propargylamino, piperidinyl,piperazinyl, morpholinomethyl, pyrrolidinylmethyl, piperazinylmethyl,piperidinylmethyl, pyridinylmethyl, thienylmethyl, thiazolylmethyl,oxazolylmethyl, pyrimidinylmethyl, quinolylmethyl, isoquinolinylmethyl,imidazolylmethyl, benzimidazolylmethyl, furylmethyl, pyrazinylmethyl,aminocarbonylamino, methylaminocarbonylamino,dimethylaminocarbonylamino, ethylaminocarbonylamino,diethylaminocarbonylamino, methylsulfonylamino, ethylsulfonylamino,aminosulfonylamino, methylaminosulfonylamino,dimethylaminosulfonylamino, ethylaminosulfonylamino, anddiethylaminosulfonylamino; Ar¹ is selected from the group consisting ofphenyl, biphenyl, and naphthyl, wherein: the phenyl, biphenyl, andnaphthyl are optionally substituted with one or more radicalsindependently selected from the group consisting of methylthio,methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl,methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl,ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl,difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl,chloromethyl, allyl, vinyl, ethynyl, propargyl, methoxy, ethoxy,propyloxy, n-butoxy, amino, methylamino, ethylamino, dimethylamino,diethylamino, aminomethyl, aminoethyl, N-methyl, N-phenylamino,phenylamino, diphenylamino, nitro, and chlorosulfonyl; and HetAr² isselected from the group consisting of pyridinyl and pyrimidinyl,wherein: the pyridinyl and pyrimidinyl are optionally substituted withone or more radicals independently selected from the group consisting ofmethylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo,methyl, ethyl, isopropyl, tert-butyl, isobutyl, methoxy, ethoxy,phenoxyl, benzoxyl, phenethyl, trifluoromethyl, fluoromethyl,difluoromethyl, amino, benzylamino, propargylamino, cyclopropylamino,cyclobutylamino, cyclopentylamino, and cyano.
 4. A compound, salt, ortautomer of claim 3, wherein: R² is selected from the group consistingof hydrido, methyl, ethyl, amino, aminocarbonylamino,methylaminocarbonylamino, methylsulfonylamino, aminosulfonylamino, andmethylaminosulfonylamino; Ar¹ is phenyl optionally substituted with oneor more radicals independently selected from the group consisting ofmethylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo,aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano,methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,dichloromethyl, chloromethyl, methoxy, ethoxy, propyloxy, n-butoxy,amino, methylamino, ethylamino, dimethylamino, diethylamino,aminomethyl, aminoethyl, N-methyl, N-phenylamino, phenylamino,diphenylamino, nitro, and chlorosulfonyl; and HetAr² is selected fromthe group consisting of pyridinyl and pyrimidinyl, wherein: thepyridinyl and pyrimidinyl are optionally substituted with one or moreradicals independently selected from the group consisting of methylthio,methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl,isopropyl, tert-butyl, isobutyl, methoxy, ethoxy, phenoxyl, benzoxyl,trifluoromethyl, fluoromethyl, difluoromethyl, amino, propargylamino,and cyano.
 5. A compound, salt, or tautomer of claim 1, wherein R¹ ishydroxyalkyl.
 6. A compound, salt, or tautomer of claim 1, wherein R² ishydrido.
 7. A compound, salt, or tautomer of claim 2, wherein R² ishydrido.
 8. A compound, salt, or tautomer of claim 3, wherein R² ishydrido.
 9. A compound, salt, or tautomer of claim 4, wherein R² ishydrido.
 10. A compound, salt, or tautomer of claim 5, wherein R² ishydrido.
 11. A compound, salt, or tautomer of claim 1, wherein HetAr² isoptionally substituted pyridinyl.
 12. A compound, salt, or tautomer ofclaim 2, wherein HetAr² is optionally substituted pyridinyl.
 13. Acompound, salt, or tautomer of claim 3, wherein HetAr² is optionallysubstituted pyridinyl.
 14. A compound, salt, or tautomer of claim 4,wherein HetAr² is optionally substituted pyridinyl.
 15. A compound,salt, or tautomer of claim 5, wherein HetAr² is optionally substitutedpyridinyl.
 16. A compound, salt, or tautomer of claim 1, wherein: R² ishydrido, Ar¹ is optionally substituted phenyl, and HetAr² is optionallysubstituted pyridinyl.
 17. A compound, salt, or tautomer of claim 2,wherein: R² is hydrido, Ar¹ is optionally substituted phenyl, and HetAr²is optionally substituted pyridinyl.
 18. A compound, salt, or tautomerof claim 3, wherein: R² is hydrido, Ar¹ is optionally substitutedphenyl, and HetAr² is optionally substituted pyridinyl.
 19. A compound,salt, or tautomer of claim 4, wherein: R² is hydrido, and HetAr² isoptionally substituted pyridinyl.
 20. A compound, salt, or tautomer ofclaim 5, wherein: R² is hydrido, and HetAr² is optionally substitutedpyridinyl.
 21. A compound, salt, or tautomer of claim 1, wherein thecompound is 4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol.22. A pharmaceutical composition comprising a therapeutically-effectiveamount of a compound, salt, or tautomer of claim
 1. 23. A pharmaceuticalcomposition comprising a therapeutically-effective amount of a compound,salt, or tautomer of claim
 2. 24. A pharmaceutical compositioncomprising a therapeutically-effective amount of a compound, salt, ortautomer of claim
 3. 25. A pharmaceutical composition comprising atherapeutically-effective amount of a compound, salt, or tautomer ofclaim
 4. 26. A pharmaceutical composition comprising atherapeutically-effective amount of a compound, salt, or tautomer ofclaim
 5. 27. A pharmaceutical composition comprising atherapeutically-effective amount of a compound, salt, or tautomer ofclaim
 21. 28. A method of treating a TNF mediated disorder comprisingtreating a subject having or susceptible to such disorder with atherapeutically-effective amount of a compound, salt, or tautomer ofclaim
 2. 29. A method of treating a TNF mediated disorder comprisingtreating a subject having or susceptible to such disorder with atherapeutically-effective amount of a compound, salt, or tautomer ofclaim
 5. 30. A method of treating a TNF mediated disorder comprisingtreating a subject having or susceptible to such disorder with atherapeutically-effective amount of a compound, salt, or tautomer ofclaim
 21. 31. A method of treating a p38 kinase mediated disordercomprising treating a subject having or susceptible to such disorderwith a therapeutically-effective amount of a compound, salt, or tautomerof claim
 2. 32. A method of treating a p38 kinase mediated disordercomprising treating a subject having or susceptible to such disorderwith a therapeutically-effective amount of a compound, salt, or tautomerof claim
 5. 33. A method of treating a p38 kinase mediated disordercomprising treating a subject having or susceptible to such disorderwith a therapeutically-effective amount of a compound, salt, or tautomerof claim
 21. 34. A method of treating inflammation comprising treating asubject having or susceptible to inflammation with atherapeutically-effective amount of a compound, salt, or tautomer ofclaim
 2. 35. A method of treating inflammation comprising treating asubject having or susceptible to inflammation with atherapeutically-effective amount of a compound, salt, or tautomer ofclaim
 5. 36. A method of treating inflammation comprising treating asubject having or susceptible to inflammation with atherapeutically-effective amount of a compound, salt, or tautomer ofclaim
 21. 37. A method of treating arthritis comprising treating asubject having or susceptible to arthritis with atherapeutically-effective amount of a compound, salt, or tautomer ofclaim
 2. 38. A method of treating arthritis comprising treating asubject having or susceptible to arthritis with atherapeutically-effective amount of a compound, salt, or tautomer ofclaim
 5. 39. A method of treating arthritis comprising treating asubject having or susceptible to arthritis with atherapeutically-effective amount of a compound, salt, or tautomer ofclaim 21.